Imidazole compounds, processes for their preparation, pharmaceuticals based on these compounds and some intermediates

ABSTRACT

Imidazole compounds of the formula I ##STR1## in which R 1  =alkyl, 
     R 2  and R 3  =H, halogen or alkyl, 
     X=OH or an amide radical having certain substituents, processes for their preparation and pharmaceuticals based on these compounds, in particular for the prophylaxis and treatment of circulatory disturbances, especially of disturbances of the microcirculation and of the disorders resulting therefrom, 
     and some novel intermediates for the preparation of the compounds of the formula I, which are 1-methyl-, 1,2-dimethyl- and 1-ethyl-4-imidazolesulfonyl chloride.

In recent years, diseases of the circulatory system at over 50% were atthe top of all cases of death. Here, in turn, thromboemboliccomplications mainly dominated. In spite of worldwide intensive effortsto make advances in the elucidation of causes of disease,characterization and recognition of relevant risk factors anddevelopment of reliable treatment methods, to this day a satisfactorymedicinal treatment is lacking (L. Harker, in: Seminars in Thrombosisand Hemostasis, Vol. 12, No. 2, 134-155, 1986; de Gaetano et al., in:Current issues in thrombosis prevention with antiplatelet drugs, 31,517-549, 1986). The overriding aim of an antithrombotic, antiischemictreatment is the correction of the disturbed organ functions (forexample the muscle power in intermittent claudication) and thus animprovement of the quality of life by prevention of early invalidism andultimately the prevention of fatal events.

About 5% of all people over 50 years old suffer from peripheralcirculatory disturbances, of which easily 10% are in danger ofdeveloping critical ischemia of the limbs (CLI=critical limb ischemia).The incidence of CLI is about 500 to 1000 per 1 million people per year.About 60% of these patients receive a vessel replacement, but about 20%suffer the fate of primary amputation. A year later, only about 55% ofthe patients still possess both lower extremities, but already about 25%have had an amputation and the remaining patients have died. This shortaccount shows in an impressive manner the necessity of an early andeffective medicinal treatment of peripheral occlusive diseases.

The previously known imidazolesulfonamides should principally haveherbicidal or biocidal properties (cf. CA-A-1,222,752 corresponding toEP-A-96,003; EP-A-95,925, EP-A-0,298,196 and EP-A-249,938), be suitbleas textile auxiliaries or plasticizers for plastics (U.S. Pat. No.3,932,444) or, alternatively, act as carboanhydrase inhibitors (U.S.Pat. No. 2,603,649).

It has now been found that a number of novel imidazole compounds(imidazolesulfonic acids and imidazolesulfonamides) surprisingly havevery useful pharmacological properties, in particular those which enableprophylaxis and treatment of circulatory disturbances, especially ofdisturbances of the microcirculation and the disorders resultingtherefrom. They are the compounds of the following formula I; theinvention therefore relates to these compounds and their physiologicallytolerable salts.

Formula I is ##STR2## in which

R¹ is (C₁ -C₆)-alkyl,

R² and R³ are identical or different and in each case are

H,

halogen (F, Cl, Br or I), preferably Cl, or (C₁ -C₃)-alkyl,

X is OH

or an amino group of the formula II ##STR3## in which

R⁴ is H or

(C₁ -C₇)-, preferably (C₁ -C₄)-alkyl, optionally substituted by CN, NH₂or COOH,

R⁵ is a (C₁ -C₈)-, preferably a (C₁ -C₅)-alkyl radical, in which--if ithas more than 1 carbon atom--there can also be a phenylene radicalbetween 2 carbon atoms and its (aliphatic) carbon atoms are substitutedby 1 or more of the following groups:

OH,

(C₁ -C₃)-alkoxy

phenyl, optionally substituted by 1-3 OH,

(C₁ -C₃)-alkoxy groups, (C₁ -C₃)-alkoxy-COOH, and/or

(C₁ -C₃)-alkoxy-COO(C₁ -C₄)-alkyl

COOH,

COO(C₁ -C₃)-alkyl,

CONH₂,

CN,

(C₂ -C₅)-alkynyl,

NH₂, ##STR4## monocyclic 5- to 7-membered saturated orunsatured--preferably saturated--heterocyclic radicals having 1 nitrogenatom and optionally also an additional nitrogen, oxygen or sulfur atomon the ring,

optionally substituted by (C₁ -C₃)-alkyl,

phenyl,

phenylalkyl having 1-3 carbon atoms in the alkyl moiety,

OH, and/or

oxo (=O), including the open and cyclic ketal forms having 2-6 carbonatoms in the ketal moiety,

and in which the ring sulfur atom--if present--can also be oxidized tothe sulfoxide (SO) or sulfone (SO₂) form,

or in which

R⁴ and R⁵, together with the amide nitrogen atom to which they arebonded, form a--preferably saturated--5- to 7-membered heterocyclic ringwhich, apart from the amide nitrogen, can additionally contain a furtherheteroatom from the group comprising N, O and S,

where, however, the unsubstituted morpholine ring ##STR5## is excluded

and the heterocyclic ring can otherwise be substituted by the followinggroups:

(C₁ -C₃)-alkoxy,

phenylalkyl having 1-4 carbon atoms in the alkyl moiety,

phenyl, optionally substituted by 1 or more--preferably only 1--of thegroups:

(C₁ -C₃)-alkyl,

OH,

(C₁ -C₃)-alkoxy,

(C₁ -C₃)-alkoxy-COOH,

(C₁ -C₃)-alkoxy-COO(C₁ -C₄)alkyl, ##STR6## in which R^(1') has the samemeaning as R¹ and can additionally also be H, and

R² and R³ have the abovementioned meaning,

and the ring sulfur atom--if present--can also be oxidized to thesulfoxide (SO) or sulfone (SO₂) form.

Preferred compounds of the formula I are those in which at least one ofthe following features are present:

a) R¹ is CH₃ or C₂ H₅,

b) R² and R³ are identical or different and in each case are H, Cl orCH₃ and

c) the --SO₂ X radical is situated in the 2- or 4-position of theimidazole ring.

Among the compounds of the formula I, the sulfonamides are furthermorepreferred; i.e. the compounds where ##STR7## where the radicals R⁴ andR⁵ preferably have the following meaning:

R⁴ is H and

R⁵ is a (C₂ -C₅)-alkyl radical in which there is optionally a phenyleneradical between 2 carbon atoms and its (aliphatic) carbon atoms aresubstituted by a total of 1 or 2--preferably only by 1--of the followinggroups:

hydroxyphenyl C₆ H₄ OH

CN

(C₂ -C₃)-alkynyl

NH₂

    ______________________________________                                                          in which R.sup.6 is identical or different                  NHR.sup.6         radicals of the type                                        N(R.sup.6).sub.2  (C.sub.1 --C.sub.3)-alkyl,                                                    (C.sub.2 --C.sub.4)-alkoxyalkyl and benzyl;                 ______________________________________                                    

a monocyclic 5- to 6-membered saturated heterocyclic radical from thegroup comprising: ##STR8## or R⁴ and R⁵, together with the amidenitrogen atom to which they are bonded, form a saturated 6-memberedheterocyclic ring of the type ##STR9##

Among the sulfonamides, again those having separate radicals R⁴ and R⁵are somewhat preferred compared to those having--together with the amidenitrogen--R⁴ +R⁵ closed to give a ring.

Particularly preferred compounds of the formula I are

N-(2-morpholinoethyl)-1-methyl-2-imidazolesulfonamide=compound of theformula I in which

R¹ =CH₃,

R² =R³ =H,

the SO₂ X group is in the 2-position and ##STR10## and also

N-(3-morpholinopropyl)-1-methyl-4-imidazolesulfonamide=compound of theformula I in which

R¹ =CH₃,

R² =R³ =H,

the SO₂ X group is in the 4-position and ##STR11##

Examples of suitable physiologically tolerable salts are:

--if in the compounds of the formula I acidic groups are present (inparticular if X=OH):

Na, K and NH₄ salts etc.;

--if in the compounds of the formula I basic groups are present:

hydrochlorides, salts with physiologically tolerable organic acids(acetic acid, maleic acid, fumaric acid etc.), etc.

Some examples of compounds of the formula I according to theinvention--both not particularly preferred and preferred--are:

1-methyl-4-imidazolesulfonic acid,

1-ethyl-4-imidazolesulfonic acid,

1-methyl-2-imidazolesulfonic acid,

5-chloro-1-methyl-4-imidazolesulfonic acid,

2-fluoro-1-methyl-4-imidazolesulfonic acid

4-chloro-1-methyl-5-imidazolesulfonic acid,

1-methyl-5-imidazolesulfonic acid,

1,2-dimethyl-5-imidazolesulfonic acid,

N-(3-morpholinopropyl)-1-methyl-4-imidazolesulfonamide,

N-(2-morpholinoethyl)-1-methyl-4-imidazolesulfonamide,

N-(4-morpholinobutyl)-1-methyl-4-imidazolesulfonamide,

N-(5-morpholinopentyl)-1-methyl-4-imidazolesulfonamide,

N-(3-morpholino-2-methyl-1-propyl)-1-methyl-4-imidazolesulfonamide,

N-(3-thiomorpholinopropyl)-1-methyl-4-imidazolesulfonamide,

N-butyl-N-(3-morpholino-1-propyl)-1-methyl-4-imidazolesulfonamide,

N-(2-piperidinoethyl)-1-methyl-4-imidazolesulfonamide,

N-[3-(2-methylpiperidino)propyl]-1-methyl-4-imidazolesulfonamide,

N-(5-piperidinopentyl)-1-methyl-4-imidazolesulfonamide,

N-[8-aza-1,4-dioxaspiro(4,5)decyl]-1-methyl-4-imidazolesulfonamide,

N-(2-pyrrolidinoethyl)-1-methyl-4-imidazolesulfonamide,

N-[2-(1-methyl-2-pyrrolidinyl)-ethyl]-1-methyl-4-imidazolesulfonamide,

N-<3[bis(2-methoxyethyl)amino]propyl>-4-imidazolesulfonamide,

N-[4-(4-hydroxyphenyl)piperazino]-1-methyl-4-imidazolesulfonamide,

N-[3-(4-benzyl-1-piperazinyl)propyl]-1-methyl-4-imidazolesulfonamide,

N-[3-(4-methylpiperazino)propyl]-1-methyl-4-imidazolesulfonamide,

N-[3-(N-benzyl-N-methylamino)-1-propyl]-1-methyl-4-imidazolesulfonamide,

N-(3-morpholinopropyl)-1-methyl-2-imidazolesulfonamide,

N-(2-morpholinoethyl)-1-methyl-2-imidazolesulfonamide,

N-(3-morpholinopropyl)-4-chloro-1-methyl-5-imidazolesulfonamide,

N-(3-mprholinopropyl)-5-chloro-1-methyl-4-imidazolesulfonamide,

N-(3-morpholinopropyl)-1,2-dimethyl-4-imidazolesulfonamide,

N-(5-morpholino-1-pentyl)-5-chloro-1-methyl-4-imidazolesulfonamide,

N-(3-morpholinopropyl)-1-propyl-4-imidazolesulfonamide,

N-(3-morpholinopropyl)-1-propyl-5-imidazolesulfonamide,

N-(3-morpholinopropyl)-1-n-butyl-4-imidazolesulfonamide,

N-(3-morpholinopropyl)-1-n-butyl-5-imidazolesulfonamide,

N-(3-morpholinopropyl)-1-ethyl-4-imidazolesulfonamide,

N-(1,3-dimorpholino-2-propyl)-1-methyl-4-imidazolesulfonamide,

N-[4-(4-hydroxyphenyl)piperazino]-5-chloro-1-methyl-4-imidazolesulfonamide,

1-(1-methyl-5-chloro-4-imidazolesulfonyl)-4-[4-(1-methyl-5-chloro-4-imidazolesulfonyloxy)phenyl]piperazine,

4-(1-methyl-4-imidazolesulfonyl)tetrahydro-4H-1,4-thiazine

1-[3-(1-methyl-5-imidazolesulfonyl)aminopropyl]-2-pyrrolidinone,

N-(3-methoxypropyl)-1-methyl-4-imidazolesulfonamide,

N-(4-hydroxyphenethyl)-1-methyl-4-imidazolesulfonamide,

N-(4-hydroxyphenethyl)-5-chloro-1-methyl-4-imidazolesulfonamide,

1,6-bis(5-chloro-1-methyl-4-imidazolesulfonamido)hexane,

N-(2-cyanoethyl)-1-methyl-4-imidazolesulfonamide,

N-(5-cyanopentyl)-1-methyl-4-imidazolesulfonamide,

N-(3-propargyl)-1-methyl-4-imidazolesulfonamide,

4-[2-(1-methyl-4-imidazolesulfonyl)aminoethyl]phenoxyacetic acid,

4-[2-(5-chloro-1-methyl-4-imidazolesulfonyl)aminoethyl]phenoxyaceticacid,

N-(3-morpholino-1-propyl)-1-methyl-5-imidazolesulfonamide,

1,6-bis(1-methyl-4-imidazolesulfonamido)hexane,

N-[3-(1-piperazinyl)propyl]-1-methyl-4-imidazolesulfonamide,

4-methyl-4-[3-(1-methyl-4-imidazolesulfamoyl)-1-propyl]morpholiniumiodide,

4-(1-methyl-4-imidazolesulfonyl)tetrahydro-4H-1,4-thiazine-1,1-dioxide,

Ethyl4-[4-(5-chloro-1-methyl-4-imidazolesulfonyl)piperazin-1-yl]phenoxyacetate

N-(6-aminohexyl)-1-methyl-4-imidazolesulfonamide,

N-(3-aminopropyl)-1-methyl-4-imidazolesulfonamide,

N-(3-thiomorpholinopropyl)-1-methyl-4-imidazolesulfonamide-S-oxide,

N-(3-methylamino-1-propyl)-1-methyl-4-imidazolesulfonamide,

N-[4-(morpholinomethyl)benzyl]-1-methyl-4-imidazolesulfonamide,

N-(3-dibenzylaminopropyl)-1-methyl-4-imidazolesulfonamide,

N-(3-dimethylaminopropyl)-1-methyl-4-imidazolesulfonamide,

N-(3-N-ethyl-N-isopropylaminopropyl)-1-methyl-4-imidazolesulfonamide,

N-[bis(2-cyanoethyl)]-1-methyl-4-imidazolesulfonamide,

N-[2-(2-pyridyl)ethyl]-1-methyl-4-imidazolesulfonamide,

N-(5-carboxypentyl)-1-methyl-4-imidazolesulfonamide and

N-(5-acetylpentyl)-1-methyl-4-imidazolesulfonamide.

The compounds of the formula I and their physiologically tolerable saltsare prepared according to the invention by

a) converting an imidazole derivative of the general formula III##STR12## in which R¹, R² and R³ have the meaning mentioned in formulaI, and one of the positions 4 or 5 is unsubstituted, by sulfonation bymeans of sulfuric acid or oleum, preferably at temperatures of about150°-180° C., into the compounds of the formula Ia according to theinvention ##STR13## in which R¹, R² and R³ likewise have the meaningmentioned in formula I, or by

b) converting an imidazole derivative of the general formula IV,##STR14## in which R¹ and R² have the meaning mentioned in formula I,one of the positions 4 or 5 carries a halogen atom (Cl, Br or I) and theother is unsubstituted, by sulfonation and subsequent hydrogenolyticdehalogenation by means of noble metal catalysts, preferably at hydrogenpressures of about 1-5 bar in polar solvents such as alcohol and/orwater and room temperature to about 60° C., into a compound of theformula Ib ##STR15## (meaning of R¹ and R² as in formula I)

--the temporary protection of the 4- or 5-position in this case thusprevents the sulfonation in this position and therefore leads to uniformproducts--or by

c) hydrolyzing an imidazole derivative of the general formula V,##STR16## in which R¹, R² and R³ have the meaning mentioned in formula Iand Y is halogen, preferably chlorine, to give the sulfonic acids of theformula Ia according to the invention with the meanings for R¹, R² andR³ mentioned there--preferably by means of water at room temperature, orby

d) oxidizing an imidazole derivative of the general formula VI or VI'##STR17## in which R¹, R² and R³ have the meaning mentioned in formulaI, to give the corresponding imidazolesulfonic acid (formula Ia),

preferably by oxidizing by the process according to EP-A-95,925 withchlorine to give an intermediate imidazolesulfonyl chloride and thendirectly hydrolyzing in aqueous medium, or by

e) reacting an imidazolesulfonyl halide of the general formula V (seevariant c) with an amine of the formula H-II ##STR18## in which R⁴ andR⁵ have the same meaning as in formula II, to give the sulfonamides ofthe formula Ic according to the invention ##STR19## in which R¹ to R⁵have the meanings mentioned in the formulae I and II.

On the one hand, this reaction can be carried out in the absence ofadditional acid scavengers, the corresponding hydrochlorides beingformed in the conversion of di- and polyamines, which can either beisolated as such or converted into the free bases, which in turn caneither be isolated as such or converted into other salts, for examplethose of fumaric acid.

On the other hand, the reaction can also be carried out in the presenceof acid scavengers, for example an excess of the amine H--N(R⁴)R⁵ to bereacted (formula H-II), a lower tertiary amine such as triethylamine, orinorganic basis such as potassium carbonate.

The sulfonamide formation can be carried out in an anhydrous solventwhich is inert to the reaction components, preferably acetonitrile ordichloromethane, in a suitable procedure, but also in protic solvents,for example water or phenol, in each case at temperatures between about-30° C. and the boiling temperatures of the solvent used, but preferablybetween about 0° C. and 30° C.

The amines of the formula H-II used as starting materials in theseprocess variants are for the most part known or can be prepared bymethods which are known from the literature, predominantly byhydrogenation or reduction of appropriately substituted nitriles. Incases in which hydrogenation is not applicable, resort can be made, forexample, to the phthalimide method. Thus, as an example it may bementioned that N-(3-bromopropyl)phthalimide reacts with thiomorpholineto give N-(3-thiomorpholinopropyl)phthalimide, which can be converted byhydrazine and subsequent action of hydrochloric acid into thehydrochloride of N-(3-aminopropyl)thiomorpholine.

The compounds of the formula I and their physiologically tolerable saltsare furthermore prepared according to the invention by

f) reacting imidazole derivatives of the general formula VII, ##STR20##in which R¹ and R² have the meaning indicated in formula I and Y isidentical or different halogen atoms (Cl, Br or I), with amines of theformula H-II and then subjecting the products to hydrogenolyticdehalogenation, preferably over noble metal catalysts, such as palladiumon carbon, in order to obtain the sulfonamides unsubstituted in the 4-or 5-position of the formula Id ##STR21## (meaning of R¹, R², R⁴ and R⁵as in formulae I and II), or by

g) reacting an imidazolesulfonyl halide of the general formula V (seevariant c) with a trialkylsilylamine of the formula VIII ##STR22## whereR⁴ and R⁵ have the meaning mentioned in formula II and a preferred C₁-C₃)-alkyl radical is the methyl radical, in order to obtain thesulfonamides of the formula Ic according to the invention (see variante).

The silylated amines can be used either as pure compounds or as crudeproducts prepared freshly--for example by means of MSTFA(N-methyl-N-trimethylsilyltrifluoroacetamide). The reaction with therespective imidazolesulfonyl halide V is usually carried out in inertsolvents, such as dichloromethane or acetonitrile, at temperaturesbetween about -30° to about 120° C., preferably between about -30° C.and the boiling point of the solvent. This process directly yields thefree base and is additionally indicated in the case of less reactive andsensitive compounds.

h) Compounds according to the invention as in formula I (whereX=--N(R⁴)R⁵, where R⁴ carries at least one NH₂ group and/or R⁵ carriesat least one primary or secondary amino group) and their physiologicallytolerable salts can additionally be prepared by reacting amines of theformula H--N(R⁴)R⁵, which on their radicals R⁴ and/or R⁵ carry at leastone N-protected--preferably N-benzylated--appropriate amino group, withthe imidazolesulfonyl halides of the formula V (see variant c), asdescribed under e), and subsequently setting the resulting sulfonamidesfree from the protecting group(s), in the case of the N-benzylprotective group preferably by hydrogenolysis at low hydrogen pressures(about 1-5 bar), slightly elevated temperatures (room temperature toabout 60° C.) and in ethanolic-aqueous ammonia solution over noble metalcatalysts, such as palladium on carbon.

From the number of protecting groups which are suitable for theprotection of the second amino group from attack by an imidazolesulfonylhalide and can be removed again, the following--apart from the preferredbenzyl group already mentioned--may additionally be emphasized:triphenylmethyl, trifluoroacetyl, benzyloxycarbonyl,tert.-butyloxycarbonyl, phthalyl, formyl and acetyl.

i) Those imidazole derivatives of the formula I where X=--N(R⁴)R⁵, whereat least one of the radicals R⁴ and R⁵ carries one or more primary aminogroups, can furthermore be prepared by reacting imidazolesulfonylhalides of the formula V (see variant c) with appropriate aminonitrilesanalogously to the procedure as in varient e) and reducing theimidazolesulfonylaminonitriles thus obtained to the corresponding aminocompounds, preferably by catalytic hydrogenation using noble metalcatalysts such as palladium on carbon in alcoholic-ammoniacal solutionat elevated hydrogen pressure (about 2-5 bar) at room temperature toslightly elevated temperature (up to about 60° C.).

j) Imidazole derivatives of the formula I where X=--N(R⁴)R⁵, where R⁵ isthe carrier of a quaternary amino group --N.sup.⊕ (R⁶)₃, in which theradicals R⁶ can be identical or different, can additionally be preparedas follows:

The compounds of the formula I with tertiary amino groups --N(R⁶)₂ as asubstituent of R⁵ are quaternized by means of an alkylating agent suchas an alkyl halide, preferably iodomethane, a sulfuric acid ester,preferably dimethyl sulfate or an arylsulfonic acid ester, preferablymethyl p-toluenesulfonate, in solvents such as nitromethane,acetonitrile, alcohols or aqueous-alcoholic solutions, preferably in therange from room temperature up to the boiling temperature of thesolvent.

k) Other substances according to the invention can be prepared byoxidizing imidazole derivatives of the general formula I whereX=--N(R⁴)R⁵, where R⁵, or R⁴ and R⁵ are together a carrier of at leastone sulfide group, preferably in the form of a thiomorpholine ring, tothe corresponding sulfoxides or sulfones. Suitable oxidants for this aresodium iodate in aqueous-methanolic solution or peroxides such asm-chloroperoxybenzoic acid, peracetic acid or hydrogen peroxide insolvents such as chloroform or acetic acid or water.

l) Among the compounds of the formula I, some can be synthesized byalkylating imidazole derivatives of the general formula I whereX=--N(R⁴)R⁵, where R⁵ or R⁴ and R⁵ together carry at least one arylradical, which is substituted by one or more phenolic hydroxyl groups,with alkylating reagents, preferably ω-halo-fatty acid derivatives, tothe corresponding phenol ethers in the presence of basic compounds, suchas sodium hydroxide, in a polar solvent, such as ethanol, in thetemperature range from about 0° C. up to the boiling point of thesolvent.

If the products are derivatives of the ω-fatty acid esters, these canfurthermore also be subjected to acidic or alkaline hydrolysis understandard conditions or aminolysis using ammonia solutions or solutionsof lower primary or secondary amines, preferably methylamine, in orderto give the corresponding carboxylic acids or carboxamides.

m) These phenolic imidazole derivatives mentioned under l) can also bereacted with acylating agents such as alkylcarbonyl chlorides,preferably those of acetic, propionic or butyric acid, with arylsulfonylchlorides, preferably benzene- or toluenesulfonyl chloride, and withimidazolesulfonyl halides of the general formula V (see variant c), inwhich R¹ can additionally still be hydrogen, to give the correspondingphenol esters. In this case, basic anhydrous conditions are expedient.

The compounds of the formula I and their physiologically tolerable saltsare very highly suitable as a result of their useful pharmacologicalproperties for use as medicines.

The invention therefore also relates to medicaments containing at leastone compound of the formula I and/or at least one of its physiologicallytolerable salts. The medicaments are preferably suited to theprophylaxis and/or treatment of circulatory disturbances, in particularof disturbances of the microcirculation and the disorders resultingtherefrom.

The disorders resulting from circulatory disturbances, in particularfrom disturbances of the microcirculation, are principally ischemicskeletal and/or cardiac muscle disorders, in particular intermittentclaudication, ulcer of the leg and degenerative and/or inflammatorymuscle disorders of various geneses with or without muscle atrophy,vasculitis with thrombotic events, arterial and venous blood clots (forexample thromboses, shock).

Because of the circulation-promoting action of the compounds andmedicaments according to the invention, in particular in the microregion, the compounds and medicaments are also active inarteriosclerosis, in surgical aftertreatment for the prevention ofpostoperative thromboses, for the aftertreatment of cancer to prevent orreduce formation of metastases, in the treatment of patients who areattached to heat-lung machines or renal dialysis and, finally, also ofpatients after stroke or myocardial infarct and also for healing ofwounds after traumas and exogenic noxae.

The medicaments according to the invention are in general administeredorally or parenterally, but rectal administration is in principle alsopossible. Suitable solid or liquid pharmaceutical preparations are, forexample, granules, powders, tablets, coated tablets (micro)capsules,suppositories, syrups, emulsions, suspensions, aerosols, drops orinjectable solutions in ampoule form and preparations having sustainedrelease of active compound, in whose preparation excipients andadditives and/or auxiliaries such as disintegrants, binders, coatingagents, swelling agents, glidants or lubricants, flavorings, sweetenersor solubilizers are customarily used. Examples of frequently usedexcipients or auxiliaries are magnesium carbonate, titanium dioxide,lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch,vitamins, cellulose and its derivatives, animal and vegetable oils,polyethylene glycols and solvents, such as, for example, sterile water,alcohols, glycerol and polyhydric alcohols.

The pharmaceutical preparations are preferably prepared and administeredin dosage units, each unit containing a certain dose of at least onecompound of the formula I and/or at least one correspondingphysiologically tolerable salt as the active constituent. In the case ofsolid dosage units such as tablets, capsules and suppositories, thisdose can be up to about 500 mg, but preferably about 50 to 300 mg, andin the case of injection solutions in ampoule form up to about 150 mg,but preferably about 10 to 100 mg. Only small differences exist betweenthe doses of the compounds of the formula I and of their salts.

For the treatment of an adult patient--depending on the activity of thecompounds according to formula I in humans--daily doses of about 20 to500 mg of active compound, preferably about 50 to 300 mg, are indicatedon oral administration and of about 5 to 300 mg, preferably about 10 to100 mg, on intravenous administration. Under certain circumstances,however, higher or lower daily doses may also be appropriate. Theadministration of the daily dose can be carried out either by singleadministration in the form of an individual dosage unit or else severalsmaller dosage units or by multiple administration of subdivided dosesat specific intervals.

The medicaments according to the invention are produced by bringing atleast one compound of the formula I and/or at least one of itsphysiologically tolerable salts into the or a form suitable foradministration using customary excipients and, if appropriate, additivesand/or auxiliaries.

For the production of the abovementioned pharmaceutical preparationforms, the medicaments according to the invention can also be formulatedtogether with other suitable active compounds, for exampleantithrombotics, antihyperlipidemics, analgesics, sedatives,antidepressives, antianginal agents, cardiotonics, antiarrhythmics,diuretics, antihypertensives including β-receptor and calcium blockers,plasma expanders and other vasotherapeutics.

Finally, some precursors or intermediates for the preparation of thecompounds of the formula I are also novel and therefore likewise asubject of the invention; they are the compounds

1-methyl-,

1,2-dimethyl- and

1-ethyl-4-imidazolesulfonyl chloride.

These compounds are advantageously prepared by

a) reacting 1-methyl- or 1,2-dimethyl- or 1-ethylimidazole withchlorosulfonic acid ClSO₃ H, optionally with subsequent addition ofSOCl₂, or by

b) oxidatively chlorinating 1-methyl- or 1,2-dimethyl-or1-ethyl-4-mercaptoimidazole with Cl₂.

A more detailed explanation of the two process variants:

a) The reaction with chlorosulfonic acid is expediently carried out atelevated temperature, preferably between about 130° C. and 160° C., ifpossible without aspirating the resulting hydrogen chloride.

For better reaction control, the possible subsequent addition of thionylchloride is carried out at slightly elevated temperatures, preferablybetween about 60° and 80° C., at which the reaction mixture has becomeeasily stirrable and rapid reaction of the thionyl chloride is ensured.

By pouring the reaction mixture into an ice-water mixture, theseimidazole derivatives can be precipitated as almost pure1-alkyl-4-imidazolesulfonyl chlorides, while resulting5-imidazolesulfonyl chlorides mainly remain in solution and can behydrolyzed to sulfonic acids. To avoid losses by hydrolysis of the4-imidazolesulfonyl chlorides also, rapid drying is recommended,preferably in solvents such as dichloromethane, using drying agents suchas sodium sulfate.

b) 2-mercaptoimidazoles can be oxidized with chlorine, if possible usedstoichiometrically, to give the 2-imidazolesulfonyl chlorides by methodsknown from the literature [R. G. Jones et al., J. Am. Chem. Soc. 71,4000 (1949)]. The conditions for the chlorine-oxidation of the 1-alkyl-and 1,2-dialkyl-4-mercaptoimidazoles are similar (at about -10° to +10°C. in dilute hydrochloric acid).

The following (preparation) examples are intended to serve to explainthe invention in more detail.

The structures of all compounds described below were confirmed byelemental analysis and IR and ¹ H-NMR spectra. In the following, invacuo is understood as meaning that of the water-jet pump. Silica gelplates (special 0.25 mm silica gel 60F₂₅₄, Riedel-de-Haen AG, D-3016Seelze) were used for thin-layer chromatography.

The yields indicated are not optimized.

After the preparation examples, a pharmacological section thenadditionally follows, from which the activity of the compounds accordingto the invention is clear; the pharmacological section also containscomparison values compared with the standard therapeutic pentoxifylline(=1-(5-oxohexyl)-3,7-dimethylxanthine).

(PREPARATION) EXAMPLES A) Compounds of the formula I where X=OH Example1 5-Chloro-1-methyl-4-imidazolesulfonic acid

33 g (0.28 mol) of 5-chloro-1-methylimidazole in 200 ml of fumingsulfuric acid are heated at 160°-180° C. for 4 hours. After cooling, thereaction mixture is cautiously added to ice. The product crystallizesout from the cold aqueous solution (about 1.5 l). After recrystallizingtwice from water, the title compound is obtained in the form of coarseyellowish crystals of melting point 309°-310° C.

Yield: 34 g (46.9% of theory).

Example 2 1-Ethyl-4-imidazolesulfonic acid

5.6 g (29 mmol) of 1-ethyl-4-imidazolesulfonyl chloride from Example C-2are suspended in 70 ml of water at room temperature until a clearsolution is formed. After evaporating in vacuo, the residue isrecrystallized from ethanol/water in order to give the title compound ofmelting point 278° C.

Yield: 5 g (99% of theory).

Example 3 1-Methyl-4-imidazolesulfonic acid

In an analogous manner to that described in Example 2, the titlecompound of melting point 288°-289° C., after recrystallizing fromethanol/methanol, is obtained from 1-methyl-4-imidazolesulfonyl chloridefrom Example C-1 in about 70% yield.

Example 4 1-Methyl-2-imidazolesulfonic acid

In an analogous manner to that described in Example 2, the titlecompound of melting point 234°-236° C., after recrystallization fromethanol/methanol, is obtained from 1-methyl-2-imidazolesulfonyl chloride[R. O. Roblin, jr. and J. W. Clapp, J. Am. Chem. Soc. 72, 4890 (1950)]in about 72% yield.

Example 5 4-Chloro-1-methyl-5-imidazolesulfonic acid

In an analogous manner to that described in Example 2, the titlecompound of melting point 260°-261° C. is obtained from4-chloro-1-methyl-5-imidazolesulfonyl chloride [M. H. Fisher, W. H.Nicholson and R. S. Stuart, Can. J. Chem. 39, 1336 (1961)] in about 39%yield.

Example 6 1-Methyl-5-imidazolesulfonic acid

A solution of 3.1 g (17 mmol) of 1-methyl-4-chloro-5-imidazolesulfonicacid from Example 5 in 100 ml of water is hydrogenated to constantpressure at 25° C. in the presence of 0.5 g of Pd/C catalyst withshaking at an initial pressure of 3.45 bar of hydrogen. The crystallineresidue remaining after filtering off the catalyst and evaporating thewater in vacuo is recrystallized from ethanol in order to give the titlecompound of melting point 286°-287° C.

Yield: 1.5 g (58.5% of theory).

B) Compounds of the formula I where X= ##STR23## Example 7N-(3-Morpholinopropyl)-1-methyl-4-imidazolesulfonamide (hydrochloride)

A solution of 30 g (0.17 mol) of 1-methylimidazole-4-sulfonyl chloridefrom Example C-1 in 150 ml of acetonitrile is added dropwise to asolution of 24 ml (0.17 mol) of 3-morpholinopropylamine in 50 ml ofacetonitrile (or dichloromethane). The temperature of the reactionmixture is kept at room temperature or below by external cooling withice-water. Stirring is continued for 6 h at room temperature. Theprecipitate deposited is filtered off with suction and recrystallizedfrom acetonitrile in order to give 46 g (85% of theory) of the titlecompound (hydrochloride) of melting point 207°-208° C.

To form the free base, the hydrochloride is suspended in dichloromethaneand shaken with the equivalent amount of a 1H K₂ CO₃ solution. Theresidue remaining after separating off the aqueous phase, drying andremoving the solvent in vacuo is recrystallized from acetonitrile. Thefree base then has a melting point of 138°-139° C.

Example 8 N-(3-Morpholinopropyl)-1-methyl-4-imidazolesulfonamide

16.7 g (46.5 mmol) of5-chloro-N-(3-morpholino-1-propyl)-1-methyl-4-imidazolesulfonamidehydrochloride from Example 32 are hydrogenated at 25° C. and 3.45 bar inthe presence of 3 g of Pd/C catalyst in 250 ml of water. The residueremaining after filtration and evaporation in vacuo is converted intothe free base using saturated potassium carbonate solution, extractedwith dichloromethane and recrystallized from dioxane/diisopropyl etherin order to give the crystalline title compound, identical with that asin Example 7.

Yield: 6.3 g (43% of theory).

The respective title compound of lines a is obtained from1-methyl-4-imidazolesulfonyl chloride and the amine of lines b in ananalogous manner to that in Example 7:

    ______________________________________                                                                   Melting point °C.                                                      (solvent for                                       Ex.  Name                  recrystallization)                                 ______________________________________                                        9 a: N-(2-morpholinoethyl)-1-                                                                            142-143  (EtOH)                                         methyl-4-imidazolesulfon-                                                     amide                                                                    b:   2-morpholinoethylamine                                                   10 a:                                                                              N-(4-morpholinobutyl)-1-                                                                            175-176  (CH.sub.3 CN)                                  methyl-4-imidazolesulfonamide                                                 hydrochloride                                                            b:   4-morpholinobutylamine                                                   11 a:                                                                              N-(5-morpholinopentyl)-1-                                                                           195-196  (EtOH)                                         methyl-4-imidazolesulfonamide                                                 hydrochloride                                                            b:   5-morpholinopentylamine                                                  12 a:                                                                              N-(3-morpholino-2-methyl-                                                                           164-165  (EtOH)                                         1-propyl)-1-methyl-4-                                                         imidazolesulfonamide                                                          hydrochloride                                                            b:   3-morpholino-2-methyl-1-                                                      propylamine                                                              13 a:                                                                              N-(3-thiomorpholinopropyl)-                                                                         224      (EtOH/                                         1-methyl-4-imidazolesulfonamide                                                                              MeOH)                                          hydrochloride                                                            b:   3-thiomorpholinopropylamine =                                                 N-(3-aminopropyl)thiomorpholine                                          Preparation of this starting product:                                         18 g (67 mmol) of N-(3-bromopropylphthal-                                     imide), 6.9 g (67 mmol) of thiomorpholine and                                 6.8 g (68 mmol) of triethylamine are dissolved                                in 150 ml of absolute chloroform and heated to                                reflux under argon for 3 hours. After                                         concentrating in vacuo, the residue is taken                                  up with isopropanol. The precipitate deposited                                on cooling in the ice bath is filtered off.                                   Water is added to the filtrate and it is                                      adjusted to pH 4-5 using 4 N hydrochloric                                     acid. After extracting this solution by                                       shaking dichloromethane, the aqueous                                          phase is neutralized using sodium bicarbonate                                 and concentrated in vacuo. The thin layer                                     chromatographically uniform residue remaining,                                crude N-(3-thiomorpholinopropyl)phthalimide,                                  is directly subjected to hydrazinolysis. For                                  this, 14 g (48 mmol) of this crude product                                    are dissolved in 70 ml of absolute ethanol and                                3 g (48 mmol) of 80% strength hydrazine                                       hydrate are added dropwise at 70° C., whereupon-                       a precipitate (phthalazine) soon deposits.                                    After 3 hours' reflux, a further 0.5 g                                        (8 mmol) of hydrazine hydrate is added to                                     complete the reaction and the mixture is held                                 at reflux for a further 2 hours. The reaction                                 mixture is then adjusted to about pH 1 using                                  5 ml of water and 10 ml of concentrated                                       hydrochloric acid. After heating to reflux for                                1 hour, the precipitate deposited is filtered                                 off and washed with water. The filtrate is                                    neutralized and evaporated to dryness in                                      vacuo. The salts deposited after addition of                                  ethanol are filtered off with suction. The                                    filtrate is evaporated in vacuo and the - residue (9 g) is subjected to       bulb tube                                                                     distillation. The title compound passes over                                  at 0.1 torr at an air bath temperature of                                     180° C. as a colorless oil.                                            Yield: 2 g (20% of theory)                                                    14 a:                                                                              N-[4-(morpholinomethyl)benzyl]-                                                                     272-273  (EtOH/                                         1-methyl-4-imidazolesulfon-    MeOH)                                          amide hydrochloride                                                      b:   4-(morpholinomethyl)benzylamine                                          15 a:                                                                              N-butyl-N-(3-morpholino-1-                                                                          176      (CH.sub.2 CN)                                  propyl)-1-methyl-4-imidazole-                                                 sulfonamide hydrochloride                                                b:   N-butyl-N-(3-morpholino-1-propyl)-                                            amine                                                                    16 a:                                                                              N-(2-piperidinoethyl)-1-                                                                            188-189  (CH.sub.3 CN)                                  methyl-4-imidazolesulfonamide                                                 hydrochloride                                                            b:   2-piperidinoethylamine                                                   17 a:                                                                              N-[3-(2-methylpiperidino)-                                                                          186-187  (CH.sub.3 CN)                                  propyl]-1-methyl-4-imidazole-                                                 sulfonamide hydrochloride                                                b:   3-(2-methylpiperidino)propyl-                                                 amine                                                                    18 a:                                                                              N-(5-piperidinopentyl)-1-                                                                           180-181  (i-PrOH)                                       methyl-4-imidazolesulfon-                                                     amide hydrochloride                                                      b:   5-piperidinopentylamine                                                  19 a:                                                                              N-[8-aza-1,4-dioxaspiro-                                                                            164-165  (i-PrOH/                                       (4,5)decyl]-1-methyl-4-        EtOH                                           imidazolesulfonamide                                                          hydrochloride                                                            b:   8-aza-1,4-dioxaspiro-(4,5)-                                                   decylamine                                                               20 a:                                                                              N-(2-pyrrolidinoethyl)-1-                                                                           149-150  (EtOH)                                         methyl-4-imidazolesulfon-                                                     amide hydrochloride                                                      b:   2-pyrrolidinoethylamine                                                  21 a:                                                                              N-[2-(1-methyl-2-pyrrolidinyl)-                                                                     163-164  (EtOH/                                         ethyl]-1-methyl-4-imidazole-   i-PrOH)                                        sulfonamide hydrochloride                                                b:   2-(1-methyl-2-pyrrolidinyl)-                                                  1-ethylamine                                                             22 a:                                                                              N-(3-dimethylaminopropyl)-1-                                                                        190-191  (EtOH/                                         methyl-4-imidazolesulfonamide  i-PrOH)                                        hydrochloride                                                            b:   3-dimethylaminopropylamine                                               23 a:                                                                              N-<3-[bis(2-methoxyethyl)-     oil                                            amino]-propyl>-4-imidazolesulfonamide                                    b:   3-[bis(2-methoxyethyl)amino]propyl-                                           amine                                                                    24 a:                                                                              N-(3-dibenzylaminopropyl)-1-                                                                        123-124  (EtOH/                                         methyl-4-imidazolesulfonamide  i-PrOH)                                   b:   dibenzylaminopropylamine                                                 25 a:                                                                              N-[4-(4-hydroxyphenyl)-                                                                             259-260  (EtOH/                                         piperazino]-1-methyl-4-        H.sub.2 O)                                     imidazolesulfonamide                                                     b:   4-(4-hydroxyphenyl)piperazine                                            26 a:                                                                              N-[3-(4-benzyl-1-piperazinyl)-                                                                      179-180  (EtOH)                                         propyl]-1-methyl-4-imidazole-                                                 sulfonamide hydrochloride                                                b:   3-(4-benzyl-1-piperazinyl)                                                    propylamine                                                              ______________________________________                                    

Example 27N-[3-(4-Methylpiperazino)propyl]-1-methyl-4-imidazolesulfonamidedihydrogenfumarate

In an analgous manner to that described in Example 7, the free base ofthe title compound is obtained from 1-methyl-4-imidazolesulfonylchloride and 3-(4-methylpiperazino)propylamine. The dihydrogenfumaratecrystallizing in about 42% yield after addition of twice the molaramount of ethanolic fumaric acid melts at 209°-210° C.

Example 28N-[3-(N-Benzyl-N-methylamino)-1-propyl]-1-methyl-4-imidazolesulfonamidehydrogenfumarate

In an analogous manner to that described in Example 7, the free base ofthe title compound is obtained from 1-methyl-4-imidazolesulfonylchloride and 3-(N-benzyl-N-methylamino)-1-propylamine. Thehydrogenfumarate crystallizing after addition of an equimolar amount ofethanolic fumaric acid melts at 184°-185° C.

Yield: 53.4% of theory.

The following are obtained in an analogous manner to that described inExample 7

29) N-(3-Morpholinopropyl)-1-methyl-2-imidazolesulfonamidehydrochloride, melting point 177°-178° C. (from ethanol) from1-methyl-2-imidazolesulfonyl chloride and 3-morpholinopropylamine.

30) N-(2-Morpholinoethyl)-1-methyl-2-imidazolesulfonamide hydrochloride,melting point 197°-198° C. (from ethanol) from1-methyl-2-imidazolesulfonyl chloride and 2-morpholinoethylamine.

31) N-(3-Morpholinopropyl)-4-chloro-1-methyl-5-imidazolesulfonamide,melting point 113°-114° C. (from ethanol) from4-chloro-1-methyl-5-imidazolesulfonyl chloride and3-morpholinopropylamine.

32) N-(3-Morpholinopropyl)-5-chloro-1-methyl-4-imidazolesulfonamidehydrochloride, melting point 179°-180° C. (from methanol/isopropanol)from 5-chloro-1-methyl-4-imidazolesulfonyl chloride and3-morpholinopropylamine.

33) N-(3-Morpholinopropyl)-1,2-dimethyl-4-imidazolesulfonamidehydrochloride, melting point 181°-182° C. (from ethanol) from1,2-dimethyl-4-imidazolesulfonyl chloride and 3-morpholinopropylamine.

34) N-(5-Morpholino-1-pentyl)-5-chloro-1-methyl-4-imidazolesulfonamidehydrochloride, melting point 218°-219° C. (from ethanol) from5-chloro-1-methyl-4-imidazolesulfonyl chloride and5-morpholinopentylamine.

35) N-(3-Morpholinopropyl)-1-propyl-4-imidazolesulfonamide andN-(3-morpholinopropyl)-1-propyl-5-imidazolesulfonamide as a 4,5-positionisomer mixture to be obtained from the isomer mixture of 1-propyl-4-and1-propyl-5-imidazolesulfonyl chloride from Example C-4 andN-(3-aminopropyl)morpholine in the ratio 20.4%:79.5%. This mixture canbe eluted separately by means of a mixture of water:aceticacid:acetonitrile (7.5:1.5:1) by HPLC on modified silica gel (RP 18,Merck).

36) N-(3-Morpholinopropyl)-1-n-butyl-4-imidazolesulfonamide andN-(3-morpholinopropyl)-1-n-butyl-5-imidazolesulfonamide is to beobtained as a 4,5-position isomer mixture from the isomer mixture of1-butyl-4- and 1-butyl-5-imidazolesulfonyl chlorides from Example C-5and N-(3-aminopropyl)morpholine in the ratio 68.1%:17.5%. This mixturecan be eluted separately by means of a mixture of water:aceticacid:acetonitrile (7.5:1.5:1) by HPLC on modified silica gel (RP 18,Merck).

Example 37 N-(3-Morpholinopropyl)-1-ethyl-4-imidazolesulfonamidehydrogenfumarate

Analogously to Example 7, 10 g (51 mmol) of 1-ethyl-4-imidazolesulfonylchloride from Example C-2 are reacted with 7.5 ml (51 mmol) of3-morpholinopropylamine in 200 ml of acetonitrile and the mixture iscorrespondingly worked up. The hydrochloride thus obtained is dissolvedin methanol and converted into the free base by means of an equivalentamount of methanolic sodium methylate solution. The oil remaining afterevaporating in vacuo crystallizes after addition of an equimolar amountof ethanolic fumaric acid as the hydrogenfumarate of melting point148°-149° C.

Example 38 N-(1,3-Dimorpholino-2-propyl)-1-methyl-4-imidazolesulfonamide

4 g (17.5 mmol) of 1,3-dimorpholino-2-propylamine and 3.5 g (17.5 mmol)of MSTFA [N-methyl-N-(trimethylsilyl)trifluoroacetamide] are combinedunder argon and stirred at room temperature for 17 hours. The clearsolution is then concentrated in vacuo at 40° C./0.1 torr. A solution of3.16 g (17.5 mmol) of 1-methyl-4-imidazolesulfonyl chloride in 20 ml ofabsolute dichloromethane is added at 20° C. with stirring to the oilobtained. After further stirring for 6 hours at 20° C., the solvent isdistilled off in vacuo at 20° C./18 torr. The oil remaining crystallizesfrom isopropanol. After decolorization with active carbon,recrystallization from methanol/isopropanol gives the title compound ofmelting point 191°-192° C.

Yield: 3.9 g (60% of theory).

Example 39N-(3-N-Ethyl-N-isopropylaminopropyl)-1-methyl-4-imidazolesulfonamide

A solution of 10.8 g (0.06 mol) of 1-methyl-4-imidazolesulfonyl chloridefrom Example C-1 is added dropwise at room temperature to a solution of13 g (0.06 mol) of1-trimethylsilylamino-N-ethyl-N-isopropyl-3-propylamine in 100 ml ofacetonitrile and the mixture is stirred further for 6 hours. The residueremaining after evaporating in vacuo is recrystallized from isopropanolin order to give the title compound of melting point 145°-146° C.

Yield: 5.7 g (29.2% of theory).

Example 40N-[4-(4-Hydroxyphenyl)piperazino]-5-chloro-1-methyl-4-imidazolesulfonamide

A solution of 20 g (93 mmol) of 5-chloro-1-methyl-4-imidazolesulfonylchloride in 250 ml of chloroform is added dropwise at room temperatureto 16 g (90 mmol) of 4-(4-hydroxyphenyl)piperazine in 250 ml ofchloroform. 41 ml (0.3 mol) of triethylamine are then slowly addeddropwise. When, after stirring for 6 hours at room temperature, acidchloride is no longer present by thin layer chromatography, theprecipitate formed is filtered off, washed several times with water,dried and recrystallized from acetonitrile. The title compound melts at249°-250° C.

Yield: 22 g (66.3% of theory).

Example 411-(1-Methyl-5-chloro-4-imidazolesulfonyl)4-[4-(1-methyl-5-chloro-4-imidazolesulfonyloxy)phenyl]piperazine

The mother liquors from Example 40 are evaporated in vacuo. The residueis washed with water and recrystallized from water/ethanol. The titlecompound thus obtained melts at 196°-197° C.

Yield: 3.5 g (21.1% of theory).

Example 42 4-(1-Methyl-4-imidazolesulfonyl)tetrahydro-4H-1,4-thiazine

2 g (11 mmol) of 1-methyl-4-imidazolesulfonyl chloride from Example C-1,dissolved in 20 ml of acetonitrile, are added dropwise with stirring atroom temperature to a solution of 1.51 ml (15 mmol) of thiomorpholine in50 ml of acetonitrile. The reaction mixture is subsequently stirred for6 hours, filtered and evaporated in vacuo. The residue remaining isrecrystallized from isopropanol in order to give the title compound ofmelting point 154°-155° C.

Yield: 1.37 g (50% of theory).

The following are obtained in an analogous manner to that described inExample 42:

    ______________________________________                                                                   Melting point °C.                                                      (solvent for                                       Ex.  Name                  recrystallization)                                 ______________________________________                                        43   1-[3-(1-methyl-5-imidazole-                                                                         125-126  (i-PrOH)                                       sulfonyl)-aminopropyl]-2-                                                     pyrrolidinone                                                                 from N-(3-aminopropyl)-2-                                                     pyrrolidinone                                                                 and 1-methyl-4-imidazolesulfonyl                                              chloride                                                                 44   N-(3-methoxypropyl)-1-methyl-                                                                       95-96    (i-PrOH)                                       4-imidazolesulfonamide from                                                   3-methoxypropylamine (2 mol                                                   per mol acid chloride) and                                                    1-methyl-4-imidazolesulfonyl                                                  chloride                                                                 45   N-(4-hydroxyphenethyl)-1-                                                                           207-208  (H.sub.2 O)                                    methyl-4-imidazolesulfonamide                                                 from tyramine                                                                 and 1-methyl-4-imidazolesulfonyl                                              chloride in dichloromethane                                                   instead of acetonitrile                                                  46   N-(4-hydroxyphenethyl-)-5-chloro-                                                                   170      (H.sub.2 O)                                    1-methyl-4-imidazolesulfonamide                                               from tyramine                                                                 and 5-chloro-1-methyl-4-imidazole-                                            sulfonyl chloride in dichloromethane                                          instead of acetonitrile                                                  47   1,6-bis(5-chloro-1-methyl-4-                                                                        209-210  (H.sub.2 O/                                    imidazolesulfonamido)hexane    MeOH)                                          from hexamethylenediamine                                                     and 5-chloro-1-methyl-4-                                                      imidazolesulfonyl chloride                                               48   N-(2-cyanoethyl)-1-methyl-                                                                          122-124  (EtOH)                                         4-imidazolesulfonamide                                                        from 3-aminopropionitrile                                                     and 1-methyl-4-imidazolesulfonyl                                              chloride                                                                 49   N-(5-cyanopentyl)-1-methyl-                                                                         92-94    (H.sub.2 O)                                    4-imidazolesulfonamide                                                        from 6-aminocapronitrile                                                      and 1-methyl-4-imidazolesulfonyl                                              chloride                                                                 ______________________________________                                    

Example 50 N-(3-Propargyl)-1-methyl-4-imidazolesulfonamide

A solution of 3 g (16.6 mmol) of 1-methyl-4-imidazolesulfonyl chloridefrom Example C-1 in 40 ml of dichloromethane is added dropwise withfurther cooling and with stirring to an initially introduced solution,cooled to -20° C., of 1.14 ml (16.6 mmol) of propargylamine in 30 ml ofdichloromethane. The reaction solution is then slowly allowed to warm toroom temperature. The precipitate depositing during the course of thisis filtered off with suction and recrystallized from isopropanol inorder to form the title compound of melting point 145° C.

Yield: 1.5 g (45.3% of theory).

Example 51 4-[2-(1-Methyl-4-imidazolesulfonyl)aminoethyl]phenoxyaceticacid

6.3 g (32 mmol) of 4-(2-aminoethyl)phenoxyacetic acid are added to asolution of 9.7 g (79 mmol) of potassium carbonate in 50 ml of water andthe mixture is stirred for 5 minutes. A suspension of 5.8 g (32 mmol) of1-methyl-4-imidazolesulfonyl chloride from Example C-1 in 20 ml of wateris slowly added to this suspension. The mixture is heated to 80° C. andstirred at this temperature for 2 hours. After cooling to roomtemperature, the reaction solution is acidified to pH 4 using 2Nhydrochloric acid. The precipitate deposited is separated off, washedseveral times with water and recrystallized from dilute acetic acid inorder to give the title compound of melting point 203°-204° C.

Yield: 6 g (55.2% of theory).

Example 524-[2-(5-Chloro-1-methyl-4-imidazolesulfonyl)aminoethyl]phenoxyaceticacid

In an analogous manner to that described in Example 51, the titlecompound from 5-chloro-1-methyl-4-imidazolesulfonyl chloride and4-(2-aminoethyl)phenoxyacetic acid is obtained in 29% yield. Thecompound recrystallized from water melts at 174°-175° C.

Example 53 N-(3-Morpholino-1-propyl)-1-methyl-5-imidazolesulfonamidehydrochloride

1 g (2.8 mmol) ofN-(3-morpholinopropyl)-4-chloro-1-methyl-5-imidazolesulfonamide fromExample 31 is dissolved in 130 ml of 25% strength aqueous ethanol, 0.3 gof Pd/C catalyst is added and the mixture is hydrogenated with shakingat an initial pressure of 3.45 bar until absorption of hydrogen iscomplete. The catalyst is filtered off. The filtrate is concentrated invacuo and the residue is recrystallized from ethanol. The title compoundof melting point 205°-206° C. is obtained in a yield of 0.8 g (88% oftheory).

Example 54 1,6-Bis(1-methyl-4-imidazolesulfonamido)hexane

13 g (27 mmol) of1,6-bis(5-chloro-1-methyl-4-imidazolesulfonamido)hexane from Example 47in 250 ml of 1N sodium hydroxide solution are hydrogenated over 3 g of10% strength Pd/C catalyst while shaking at an initial pressure of 3.45bar until absorption of hydrogen is complete. After separating off thecatalyst, the filtrate is evaporated in vacuo. The residue wasrecrystallized from water/methanol in order to give the title compoundas colorless crystals of melting point 153°-154° C.

Yield: 6.1 g (55% of theory).

Example 55 N-[3-(1-Piperazinyl)propyl]-1-methyl-40-imidazolesulfonamidehydrochloride

3 g (7.2 mmol) ofN-[3-(4-benzyl-1-piperazinyl)-1-propyl]-1-methyl-4-imidazolesulfonamidehydrochloride from Example 26 in a solution of 30 ml of ethanol in 150ml of 25% strength ammonium hydroxide solution are hydrogenated in thepresence of 1 g of Pd/C catalyst with shaking at an initial pressure of3.45 bar and room temperature until absorption of hydrogen is complete.After concentrating under reduced pressure, the residue isrecrystallized from ethanol in order to give the desired compound ofmelting point 174°-175° C.

Yield: 1.4 g (59% of theory).

Example 564-Methyl-4-[3-(1-methyl-4-imidazolesulfamoyl)-1-propyl]morpholiniumiodide

2 g (6.9 mmol) of N-(3-morpholinopropyl)-1-methyl-4-imidazolesulfonamidefrom Example 7 are stirred at room temperature for 8 hours in a solutionof 0.48 ml (7.6 mmol) of iodomethane in 50 ml of acetonitrile. Theprecipitate formed is separated off, washed well with acetonitrile anddried in order to give the title compound of melting point 204°-205° C.

Yield: 2.5 g (84% theory).

Example 574-(1-Methyl-4-imidazolesulfonyl)tetrahydro-4H-1,4-thiazine-1,1-dioxide

1 g (4 mmol) of4-(1-methyl-4-imidazolesulfonyl)tetrahydro-4H-1,4-thiazine from Example42 are taken up in 10 ml of chloroform and a solution of 1.39 g (8 mmol)of m-chloroperoxybenzoic acid is added dropwise at 0°-5° C. Afterwarming to room temperature, the mixture is subsequently stirred for 2hours, during which the reaction product precipitates and is filteredoff with suction and recrystallized from water. The title compound thusobtained melts at 179°-180° C.

Yield: 0.3 g (26.6% of theory).

Example 58 Ethyl4-[4-(5-chloro-1-methyl-4-imidazolesulfonyl)piperazinyl]phenoxyacetate

2 g (5.6 mmol) ofN-[4-(4-hydroxyphenyl)piperazino]-5-chloro-1-methyl-4-imidazolesulfonamidefrom Example 40 are taken up in 70 ml of ethanol, 0.22 g (5.5 mmol) ofsodium hydroxide is added, the mixture is stirred for 30 minutes and0.86 g (6 mmol) of ethyl bromoacetate is added dropwise. If, afterstirring at room temperature for 6 hours, the reaction is stillincomplete according to TLC, a further 0.42 g (2.5 mmol) of ethylbromoacetate and 0.12 g (3 mmol) of sodium hydroxide are added, and themixture is heated to 50° C. and subsequently stirred for about 10 hours.After evaporating in vacuo, the residue is taken up in dichloromethaneand washed with 2N NaOH. The organic phase is evaporated in vacuo afterdrying over sodium sulfate. The crystalline residue can berecrystallized from isopropanol. The title compound thus obtained meltsat 148°-149° C.

Yield: 0.8 g (32% of theory).

Example 59 N-(6-Aminohexyl)-1-methyl-4-imidazolesulfonamidedihydrochloride

2.6 g (10 mmol) ofN-(5-cyanopentylamino)-1-methyl-4-imidazolesulfonamide from Example 49are dissolved in 50 ml of about 5N ethanolic ammonia solution, 1 g ofRaney nickel is added and the mixture is hydrogenated with shaking at aninitial pressure of 3.45 bar until absorption of hydrogen is complete.The catalyst is filtered off. The filtrate is concentrated in vacuo. Theremaining oil is dissolved in absolute ethanol. On addition of ethanolichydrochloric acid, the title compound precipitates as a crystalline saltwhich, after separating off and drying, has a melting point of 215°-223°C.

Yield: 2.3 g (60% of theory).

Example 60 N-(3-Aminopropyl)-1-methyl-4-imidazolesulfonamidehydrochloride

In an analogous manner to that described in Example 59, the titlecompound of melting point 168°-169° C. is obtained in about 55% yieldfrom N-(3-cyanoethylamino)-1-methyl-4-imidazolesulfonamide from Example48.

Example 61 N-(3-Thiomorpholinopropyl)-1-methyl-4-imidazolesulfonamideS-oxide hydrochloride

A solution of 3.5 g (10 mmol) ofN-(3-thiomorpholinopropyl)-1-methyl-4-imidazolesulfonamide hydrochloridefrom Example 13 in 30 ml of 50% aqueous methanol is added dropwise at-5° C. to a solution of 1.9 g (9 mmol) of sodium iodate in 25 ml ofwater. A precipitate formed in the course of this goes into solutionagain after a further 20 minutes. After standing overnight, excesssodium bicarbonate is added to the reaction solution, which isevaporated to dryness in vacuo and purified by column chromatography onsilica gel using dichloromethane:methanol 9:1 to 0:10. The eluted oil isconverted into the hydrochloride using ethanolic hydrochloric acid andthe title compound thus obtained is recrystallized to give a meltingpoint of 186° C. from ethanol/methanol.

Yield: 1.2 g (32% of theory).

Example 62 N-(3-Methylamino-1-propyl)-1-methyl-4-imidazolesulfonamidehydrochloride

15 g (41.7 mmol) ofN-[3-(N-benzyl-N-methylamino)-1-propyl]-1-methyl-4-imidazolesulfonamidehydrochloride from Example 28 are hydrogenated in a solution of 100 mlof 25% strength ammonia solution and 100 ml of ethanol in the presenceof 2 g of 10% strength Pd/C catalyst. After completion of the absorptionof hydrogen and filtering off the catalyst, the filtrate is evaporatedin vacuo. The residue is recrystallized from ethanol in order to givethe title compound of melting point 169°-170° C.

Yield: 2.3 g (20.5% of theory).

C) Intermediates (imidazolesulfonyl chlorides) Example 11-Methyl-4-imidazolesulfonyl chloride

1-Methylimidazole (250 g, 3.05 mol) is added dropwise to chlorosulfuricacid (600 ml, 9.03 mol), in such a way that an internal temperature of30° C. is not exceeded, without aspirating the hydrogen chloride formed.After addition is complete, the reaction mixture is stirred at 150° C.for 6 h. Thionyl chloride (340 ml, 4.66 mol) is added at 60° C. and themixture is then heated at a bath temperature of 100° C. for 6 h. Aftercooling to room temperature, the viscous reaction mixture is poured ontosufficient ice such that that the end about 7.5 l of a water-ice mixtureremains. The precipitate deposited is filtered off with suction andbriefly sucked dry in air. It is then either dried in a thin layer in avacuum drying oven at 50° C. and 15 torr, or it is preferably taken upusing dichloromethane, dried over sodium sulfate and freed from solventin vacuo. Yield: 176 g (32% of theory) of colorless crystals wereobtained (melting point: 89°-90° C.). To remove the isomeric5-imidazolesulfonic acid formed as a by-product from the mother liquor,the latter is largely concentrated in vacuo at 15 torr in a rotaryevaporator. On addition of ethanol, an imidazolesulfonic acid mixturecrystallizes out, which can be recrystallized from ethanol.

Example 2 1-Ethyl-4-imidazolesulfonyl chloride

In an analogous manner to that described in Example C-1, the titlecompound of melting point 34°-35° C. is obtained in about 24.7% yieldfrom 1-ethylimidazole by means of chlorosulfonic acid and thionylchloride.

Example 3 1,2-Dimethyl-4-imidazolesulfonyl chloride

In an analogous manner to that described in Example C-1, the titlecompound is obtained in 30% yield from 1,2-dimethylimidazole by means ofchlorosulfonic acid and thionyl chloride. It can be recrystallized fromtoluene/cyclohexane and then has a melting point of 90°-91° C.

Example 4 1-Propyl-4-imidazolesulfonyl chloride and1-propyl-5-imidazolesulfonyl chloride

In an analogous manner to that described in Example C-1, a mixture ofthe title compound is obtained in about 57% yield from 1-propylimidazoleby means of chlorosulfonic acid and thionyl chloride, which mixture isexpediently separated in the form of their derivatives.

Example 5 1-Butyl-4-imidazolesulfonyl chloride and1-butyl-5-imidazolesulfonyl chloride

In an analogous manner to that described in Example C-1, a mixture ofthe title compounds is obtained in about 17% yield from 1-butylimidazoleby means of chlorosulfonic acid and thionyl chloride, which mixture isexpediently separated in the form of their derivatives.

The compounds of the formula I as in the examples from sections A and Bare collated in the following Table 1; if the salts were prepared in theexamples, this is also taken into account in the table. The processvariants by which the compounds in the examples concerned were preparedare furthermore also indicated in the table.

                                      TABLE 1                                     __________________________________________________________________________     ##STR24##                                          (I)                       Ex.                                                                              Proc. var.                                                                          R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                         Position of the SO.sub.2 X group                                                            X                                              __________________________________________________________________________    A)1                                                                              a     CH.sub.3                                                                         Cl H 4             OH                                             (5-position)                                                                  2  c     C.sub.2 H.sub.5                                                                  H  " "             "                                              3  c     CH.sub.3                                                                         "  " "             "                                              4  c,d   "  "  " 2             "                                              5  c     "  Cl " 5             "                                              (4-Position)                                                                  6  b     "  H  " "             "                                              B)7                                                                              e     "  "  " 4                                                                                            ##STR25##                                     8  f     "  "  " "             "                                              9  e     "  "  " "                                                                                            ##STR26##                                     10 e     "  "  " "                                                                                            ##STR27##                                     11 e     "  "  " "                                                                                            ##STR28##                                     12 e     CH.sub.3                                                                         H  H 4                                                                                            ##STR29##                                     13 e     "  "  " "                                                                                            ##STR30##                                     14 e     "  "  " "                                                                                            ##STR31##                                     15 e     "  "  " "                                                                                            ##STR32##                                     16 e     "  "  " "                                                                                            ##STR33##                                     17 e     "  "  " "                                                                                            ##STR34##                                     18 e     "  "  " "                                                                                            ##STR35##                                     19 e     CH.sub.3                                                                         H  H 4                                                                                            ##STR36##                                     20 e     "  "  " "                                                                                            ##STR37##                                     21 e     "  "  " "                                                                                            ##STR38##                                     22 e     "  "  " "                                                                                            ##STR39##                                     23 e     "  "  " "                                                                                            ##STR40##                                     24 e     "  "  " "                                                                                            ##STR41##                                     25 e     "  "  " "                                                                                            ##STR42##                                     26 e     "  "  " "                                                                                            ##STR43##                                     27 e     CH.sub.3                                                                         H  H 4                                                                                            ##STR44##                                     28 e     "  "  " "                                                                                            ##STR45##                                     29 e     "  "  " 2                                                                                            ##STR46##                                     30 e     "  "  " "                                                                                            ##STR47##                                     31 e     "  Cl " 5                                                                                            ##STR48##                                     (4-Position)                                                                  32 e     "  Cl " 4                                                                                            ##STR49##                                     (5-position)                                                                  33 e     "  CH.sub.3                                                                         " "             "                                              (2-position)                                                                  34 e     CH.sub.3                                                                         Cl H 4                                                                                            ##STR50##                                     (5-position)                                                                  35 e     C.sub.3 H.sub.7                                                                  H  " "                                                                                            ##STR51##                                        +     "  "  " 5                                                                                            ##STR52##                                     36 e     C.sub.4 H.sub.9                                                                  "  " 4                                                                                            ##STR53##                                        +     "  "  " 5                                                                                            ##STR54##                                     37 e     C.sub.2 H.sub.5                                                                  "  " 4                                                                                            ##STR55##                                                                     ##STR56##                                     38 g     CH.sub.3                                                                         "  " "                                                                                            ##STR57##                                     39 g     "  "  " "                                                                                            ##STR58##                                     40 e     "  "  " "                                                                                            ##STR59##                                     41 m     "  Cl " "                                                                                            ##STR60##                                     (5-position)                                                                  42 e     "  H  " "                                                                                            ##STR61##                                     43 e     "  "  " 5                                                                                            ##STR62##                                     44 e     "  "  " 4                                                                                            ##STR63##                                     45 e     "  "  " "                                                                                            ##STR64##                                     46 e     "  Cl " "             "                                              (5-position)                                                                  47 e     "  "  " "                                                                                            ##STR65##                                     48 e     "  H  " "                                                                                            ##STR66##                                     49 e     "  "  " "                                                                                            ##STR67##                                     50 e     "  "  " "                                                                                            ##STR68##                                     51 e     "  "  " "                                                                                            ##STR69##                                     52 e     "  Cl " "             "                                              (5-position)                                                                  53 f     "  H  " 5                                                                                            ##STR70##                                     54 f     "  "  " 4                                                                                            ##STR71##                                     55 h     "  "  " "                                                                                            ##STR72##                                     56 j     "  "  " "                                                                                            ##STR73##                                     57 k     "  "  " "                                                                                            ##STR74##                                     58 l     "  Cl " "                                                                                            ##STR75##                                     (5-position)                                                                  59 i     "  H  " "                                                                                            ##STR76##                                     60 i     "  "  " "                                                                                            ##STR77##                                     61 k     "  "  " "                                                                                            ##STR78##                                     62 h     "  "  " "                                                                                            ##STR79##                                     __________________________________________________________________________

PHARMACOLOGICAL TESTING AND RESULTS 1) Effect on the Contractility ofthe Skeletal Muscle After Chronic Ischemia

In recent years, a marked change has taken place in ideas about thepathophysiology of chronic peripheral arterial occlusive disease asscientific interest has to an increasing extent shifted from themacrocirculation to the microcirculation. Disturbances in themicrocirculation therefore manifest themselves in an undersupply ofsubstrates with tissue ischemia resulting therefrom which, in turn,leads to an impairment in the function of the extremity concerned. Thelogical consequence of this is that the target organ skeletal musclecomes more and more into the forefront. This means that the therapeuticaim of any medicinal treatment has to be the improvement or--in theideal case--the re-establishment of the normal capacity. The clinicalactivity is in fact also consistently determined in humans with the aidof the painless walking distance on the moving walkway.

The testing of the compounds according to the invention for theirfunction-improving effect was therefore carried out by measurements ofthe contractility in the ischemic skeletal muscle using the experimentalprocedure described below, the standard therapeutic pentoxyfylline beingadditionally included in the investigations as a comparison preparation(see also Okyayuz-Baklouti, I., in: Muscle Ischaemia, Functional andMetabolic Aspects, eds I. Okyayuz-Baklouti and O. Hudlicka, Dr. C. Wolfund Sohn, Munich, pp. 103-126, 1988; Okyayuz-Baklouti, I., European J.of Pharmacology 166: 75-86, 1989).

Male Wistar rats having a body weight of 380 to 410 g were used asexperimental animals. Under hexobarbital anesthesia (®Evipan--sodium,200 mg/kg BW (=body weight) i.p.), a unilateral ligature of the rightfemoral artery was applied to the animals in the groin. After sprinklingpenicillin sulfonamide powder for antibiotic wound care, the smalloperation wound was closed and the animals were continuously observeduntil they were completely awake. One week later, the administration ofsubstance began by oral administration using a stomach tube (6 mg/kg BW,carboxymethylcellulose-sodium suspension) and was continued for 7 days(single administration per day, about 7h30 to 8h30). The contractilitywas measured 24 h after the last administration of substance in order toexclude acute effects, to be precise by the following experimentalprotocol:

The animals were anesthetized with ®Nembutal (pentobarbital--sodium, 35mg/kg BW i.p.), the muscles of the extremity concerned were exposed(gastrocnemius-plantaris-soleus group) and the tendon was tied to apressure transducer (Rhema Z6, Rhema, Hofheim) having a preload of 50 g.Superfusion with physiological saline solution (37° C.) was used toavoid drying out and cooling. The mean arterial blood pressure wasrecorded continuously via Statham (=blood pressure measuring device) bymeans of a cannulated caroted artery to control the physiological statusof the animals during the experiment. All animals breathed spontaneouslyby means of an inserted tracheal tube.

After these preparations, the muscle was made to contract (Stimulator I,Hugo Sachs, Federal Republic of Germany) by direct electricalstimulation (2.5 mA, 2 Hz). The absolute contractility in grams atvarious times of stimulation was used as the measured parameter. Theinitial contractility of the chronic-ischemic skeletal muscle onlydiffers insignificantly in this case (scatter of the experiments) fromthat of the normal muscle. Since, however, the undersupplied muscletires more rapidly, the contractility falls during the stimulationinterval of 5 minutes chosen here significantly more rapidly andstrongly than in the normal non-ischemic muscle. If the maximumcontractility at the start of stimulation is now divided by the residualforce remaining after 5 minutes' tiring stimulation, a "tiring index TI"for the muscle concerned can be calculated; the ability to tire here islarger the larger TI is numerically. Thus, the TI for the normal muscletreated only with the vehicle varies, depending on the experiment,between 1.78 and 3.29 (see Table 2). The ability to tire of the ischemicmuscle is around 40 to 60% higher.

In Table 2, the TI of the normal muscle was compared with the TI of theischemic treated muscle as this, most clearly, reflects a possibleimprovement of the function in the direction of normalization. Thismeans that the smaller the numerical value of the percentage change, themore effective is the respective preparation, i.e. a percentage changehaving, for example, a negative sign means an even lower ability to tirein comparison to the non-ischemic untreated muscle. 4 to 6 individualexperiments were carried out for each test preparation.

2) Antithrombotic Activity

An important factor in the genesis and the course of peripheral arterialocclusive diseases and other indications claimed for this substancegroup are thrombotic events. Thus, the compounds according to theinvention were tested for inhibition of laser-induced thrombosis (cf.for this: Seiffge, D. and Kremer, E., Thromb. Res. 42, 331-341, 1986):

These investigations were carried out on female Sprague-Dawley ratshaving a body weight of about 200 g. The animals were premedicated with0.1 mg of atropine sulfate s.c. and anesthetized with 100 mg of ketaminehydrochloride and 4 mg of xylazine per kg BW i.p. Arteriole and venulesof the mesentery covered with a layer of degassed paraffin oil andhaving a diameter of about 13 lm were used for the investigation. Thebeam of a 4 W argon laser (Spectra-Physics, Darmstadt) was broughtcoaxially into the inverted beam of a microscope (ICM 405, LD®Epiplan40/0.60, Zeiss, Oberkochen) by means of a beam-adapting and adjustingunit. The wavelength used was 514.5 nm with a power above the objectiveof 30 mW. The exposure time per individual pulse lasted 1/15 sec. Allmeasuring operations were recorded by video camera (®Trinicon tubes,Sony, Cologne) and stored on a recorder (®Sony U-matics 3/4"). The testsubstances were administered orally to the experimental animals invarious dosages one hour, on i.v. administration 10 min, before startingthe experiment; control animals received the same amount of placebo. Thesubstances were administered as a single administration once during theday or once during the day over the course of several days. Forevaluation, the number of laser pulses which are needed in order toproduce a thrombosis on the wall of a minimum size of half the vesseldiameter were counted. This means the larger the number of laser pulsesthe more effective are the preparations in this test. The percentageinhibition of thrombosis is indicated in Table 3.

3) Acute Toxicity

The determination of the LD50 ranges was carried out in standard fashionby means of the mortality occurring in the course of 7 days in NMRI miceafter single intravenous (i.v.) or intraperitoneal (i.p.) administration(NMRI=NIH Medical Research Institute). The values are likewisesummarized in Table 3.

4) Additional Special Tests

The clear superiority of the compounds according to the invention, inparticular compared to the preparation most frequently employedtherapeutically for the treatment of peripheral circulatorydisturbances, pentoxyfylline, could also be confirmed impressively inother special tests.

An important advantage of the substances according to the invention, forexample the compound from Example 7, is that they inhibit thrombosis inhyperlipidemic, spontaneously hypertensive and, thus, stroke-prone ratsand in atherosclerotic rabbits. Thus, the substance from Example 7inhibits the laser-induced thrombosis after daily administration of 10or 30 mg/kg for 7 days in hyperlipidemic hypertensive rats by 18 or 32%respectively and in atherosclerotic rabbits after daily administrationof 30 mg/kg for 14 days by 36%.

Furthermore, the substances according to the invention not only inhibitlaser-induced thrombus formation, but moreover they, particularly thesubstance of Example 7, also inhibit photochemically-induced thrombosis.In this model, rats were anesthetized as described above under 2). Theinvestigations were carried out on mesenterial arterioles having adiameter of 11 to 50 lm. A thrombosis was induced in a modification inaccordance with a method known from the literature (Herrmann, K. H.Microvasc. Res. 26, 238-249, 1983) and is based on the photochemicalrelease of singlet oxygen, which leads locally to an endothelial lesion.The animals to be investigated received an intravenous injection of 0.3ml of a 10% strength solution of fluorescein in isothiocyanate--Dextran70 (FITC--Dextran 70 s, Sigma, Munich). The arterole was looked forunder the microscope and centered in the observation field. TheFITC--Dextran in the blood vessel was then excited using a special lampand filter device (excitation 490 nm, emission 510 nm). For evaluationof thrombus formation, the time was taken which extended from the pointof excitation to the formation of a first thrombus on the wall. 5vessels in each animal were examined in this manner. It emerged that thethrombosis was inhibited in a dose-dependent and statisticallysignificant manner by the compound from Example 7 (1, 3, 10 mg/kg p.o.:69, 75, 130%). In comparison thereto, pentoxyfylline only caused aninhibition of 29, 18 and 68% at 1, 3 and 10 mg/kg p.o. After i.v.administration of 3 or 10 mg/kg of the compound from Example 7, thethrombosis was inhibited by 36% or 56% respectively; and on i.v.administration of 3 or 10 mg/kg of pentoxyfylline by 3% or 38%respectively.

Using laser-Doppler flow measurements (LDF), the erythrocyte flux (thenumber of cells flowing past under the laser beam x their velocity) canbe measured in a noninvasive and continuous manner in the capillary bedof the skeletal muscle of the rat (perimed PF2 laser-Doppler flowmeter,Perimed, Sweden). However, this technique does not indicate absolutevalues of the circulation but qualitative changes in volts, where,however, the signal obtained correlates linearly with the flux. Theapparatus was set as follows: 12 kHz, gain 10, time constant 1.5 sec,37° C. The right femoral artery of male Wistar rats having a body weightof 380-430 g was exposed and the skin and the connective tissue wasdissected away over a small muscle area (anterior tibia). The probe wasplaced about 1 mm above this area. As soon as the curve had stabilized,the femoral artery was occluded with the aid of a clamp, whereupon theLD curve in the muscle supplied by this vessel fell rapidly then, as aresult of the spontaneous opening of collateral vessels, rose againslightly and finally settled down to a strongly reduced level comparedto the starting value (residual circulation in the acutely ischemicmuscle about 25%). At this point, the test substances were infusedintravenously in aqueous solution (0.03 and 0.6 mg/kg/min). The maximumpercentage increase in the erythrocyte flux after administration ofsubstance during the occlusion (see also Okyayuz-Baklouti, I., EuropeanJ. of Pharmacology, 166: 75-86, 1989) was used as the measuringparameter for the substance activity. It emerged in this case that thecirculation in the microcirculation, for example after infusion of thecompound from Example 7, increased in a strong and dose-dependent manner(+53.3% at the lower and +80.6% at the higher dosage). In comparisonthereto, pentoxyfylline caused an increase by 24.6% at the low and by33.1% at the higher dosage. 3-7 animals were employed per preparationand dose.

The contractility in the acutely ischemic muscle was measured in asimilar experimental procedure, as described under 1). The muscle,initially normally supplied with blood, was made to contractisometrically by direct electrical stimulation (1.2 Hz, 2.5 mA). Theright femoral artery was then occluded for 5 min by means of a clamp.The contractility significantly decreases in this case owing to theinsufficient supply of substrate (infusion of the vehicle). The vesselwas then reopened and the starting contractility before the firstocclusion was attained. During the second occlusion which then followed,the preparations to be tested were administered intravenously in aqueoussolution via the jugular vein. 4-8 animals were employed per preparationand dose. The decrease in the contractility during occlusion with andwithout substance administration was compared and the percentage changewas used to evaluate the substance activity. The substances according tothe invention, for example the compound of Example 7, were alsoremarkable in this test for outstanding effects. Thus, the contractilityafter a dose of 0.03 mg/kg/min was improved by +17.2%, and after a doseof 0.3 mg/kg/min by +25.2%, while pentoxyfylline also only showedmarginal activity in this functional test.

Thus, the compounds according to the invention have outstandingactivities on the capacity of the ischemic muscle both during chronicand during acute inadequate circulation, and also favorable effects oncapillary circulation coupled with an excellent inhibition ofintravascular thrombosis.

                  TABLE 2                                                         ______________________________________                                        TIRING INDEX (TI) SKELETAL MUSCLE OF THE RAT                                  Compound TI of normal                                                                              TI of                                                    from     non-treated ischemic     Percentage                                  Example  muscle      treated muscle                                                                             change                                      ______________________________________                                         1       2.23        2.26         +1.3                                         3       2.11        2.26         +7.1                                        7/8      2.78        2.79         +0.3                                         9       2.24        2.47         10.3                                        10       2.27        2.19         -3.6                                        11       2.05        2.52         +22.9                                       13       3.29        2.95         -10.1                                       14       2.27        2.57         +13.4                                       15       1.77        1.96         +10.9                                       17       2.38        2.04         -14.3                                       19       1.98        2.20         +11.1                                       20       2.08        2.56         +23.1                                       21       1.96        2.34         +19.4                                       23       1.77        2.18         +23.1                                       25       1.98        2.11         +6.6                                        26       1.98        2.49         +25.7                                       27       1.96        2.6          +32.6                                       28       1.98        2.27         +14.6                                       29       1.98        2.74         +38.4                                       30       3.29        2.82         -14.2                                       32       2.36        2.51         +6.4                                        33       2.05        2.30         +12.2                                       34       1.98        1.98         +0.0                                        37       2.27        2.09         -7.9                                        38       1.98        2.18         +10.1                                       40       2.36        3.18         +34.7                                       41       1.84        2.18         +18.5                                       42       2.28        2.84         +24.6                                       43       1.77        2.29         +29.4                                       45       1.84        2.14         +16.3                                       46       2.19        2.05         -6.4                                        47       2.32        2.46         +6.0                                        51       2.36        2.92         +23.7                                       52       1.84        2.16         +17.4                                       53       3.29        3.18         -3.3                                        54       1.85        2.55         +37.8                                       58       2.11        2.07         -1.9                                        62       1.96        2.5          +27.8                                       Pentoxy- 2.23        3.20         +43.5                                       fylline                                                                       ______________________________________                                         For all preparations 6 mg/kg p.o. over 7 days, n = 4 - 6.                

                  TABLE 3                                                         ______________________________________                                        INHIBITION OF LASER-INDUCED THROMBOSIS IN                                     MESENTERIAL ARTERIOLES OF THE RAT AND                                         TOXICITY                                                                                           Percentage                                                                              Toxicity                                       Com-    Dose         change vs (LD.sub.50 range)                              pound   (mg/kg p.o.) control   mg/kg                                          ______________________________________                                         1      10           13        >200 i.v.                                       3      20           23                                                       7/8     10           36        >100 i.v.                                      10      10           38        >100 i.v.                                      12      20           24        >100 i.v.                                      13      20           14                                                       14      20           13        >100 i.v.                                      21      20           24                                                       25      10           22        >300 i.p.                                      26      10           24                                                       27      20           23        >100 i.v.                                      29      10           21        >100 i.v.                                      30      10           45        >100 i.v.                                      32      10           21        >200 i.v.                                      33      10           18                                                       34      10           15        >100 i.v.                                      38      10           21                                                       40      10           17        >1200 i.p.                                     43      20           15                                                       46      10           29        >1200 i.p.                                     46      30           29                                                       53      10           18        >100 i.v.                                      54      10           17        >1200 i.p.                                     56      10           24        >100 i.v.                                      57      10           19                                                       ______________________________________                                    

We claim:
 1. An imidazole compound of the formula I ##STR80## in whichR¹ is (C₁ -C₆)-alkyl,R² and R³ are identical or different and in eachcase are H, halogen, or (C₁ -C₃)-alkyl, X is an amino group of theformula II ##STR81## in which R⁴ is H, or (C₁ -C₇)-alkyl or said (C₁-C₇)-alkyl substituted by CN, NH₂ or COOH, R⁵ is (C₁ -C₈)-alkyl inwhich, when it contains more than 1 carbon atom, there can also be aphenylene radical between 2 carbon atoms and in which the aliphaticcarbon atoms are substituted by 1 or more of a heterocyclic radicalselected from the group consisting of morpholino, thiomorpholino andpiperazino, or said heterocyclic radical substituted by one or more of:(C₁ -C₃)-alkyl, phenyl, phenylalkyl having 1-3 carbon atoms in the alkylmoiety, OH or oxo, including the open and cyclic ketal forms having 2-6carbon atoms in the ketal moiety, and in which the ring sulfur atom,when present, can also be oxidized to the sulfoxide or sulfone form, orin which R⁴ and R⁵, together with the nitrogen atom to which they arebonded, form a heterocyclic ring selected from the group consisting ofmorpholino, thiomorpholino and piperazino, with the exception of theunsubstituted morpholine ring ##STR82## and in which the heterocyclicring can otherwise be substituted by the following groups: (C₁-C₃)-alkoxy, phenylalkyl having 1-4 carbon atoms in the alkyl moiety,phenyl or phenyl substituted by 1 or more of the groups: (C₁ -C₃)-alkyl,OH, (C₁ -C₃)-alkoxy, (C₁ -C₃)-alkoxy-COOH, (C₁ -C₃)-alkoxy-COO(C₁-C₄)alkyl, ##STR83## O--SO₂ --C₆ H₅, O--SO₂ --C₆ H₄ CH₃, a radical ofthe formula ##STR84## in which R^(1') is (C₁ -C₆)-alkyl or H, and R² andR³ are identical or different and in each case are H, halogen or (C₁-C₃)-alkyl, and the ring sulfur atom, when present, can also be oxidizedto the sulfoxide or sulfone form,or a physiologically tolerable saltthereof.
 2. An imidazole compound as claimed in claim 1, wherein informula I at least one of the following features are present:a) R¹ isCH₃ or C₂ H₅, b) R² and R³ are identical or different and in each caseare H, CL or CH₃ and c) the --SO₂ X radical is attached to the carbonatom in the 2- or 4-position of the imidazole ring.
 3. An imidazolecompound of the formula I as claimed in claim 1, wherein X is an aminogroup of the formula II ##STR85## where R⁴ is H andR⁵ is a (C₂-C₅)-alkyl radical or said (C₂ -C₅)-alkyl radical in which there is aphenylene radical between 2 carbon atoms and its aliphatic carbon atomsare substituted by a total of 1 or 2 of a monocyclic 6-memberedsaturated heterocyclic radical which is ##STR86## the latter of which isunsubstituted or is substituted by CH₃ or benzyl, or in which R⁴ and R⁵,together with the nitrogen atom to which they are bonded, form asaturated 6-membered heterocyclic ring which is ##STR87## the latter ofwhich is unsubstituted or is substituted by one of the followingradicals ##STR88## or a physiologically tolerable salt thereof. 4.N-(2-morpholinoethyl)-1-methyl-2-imidazolesulfonamide, which is thecompound of the formula I as claimed in claim 1 in whichR¹ is CH₃, R²and R³ are H, the SO₂ X group is attached to the carbon atom in the2-position and ##STR89## or a physiologically tolerable salt thereof. 5.N-(3-morpholinopropyl)-1-methyl-4-imidazolesulfonamide, which is thecompound of the formula I as claimed in claim 1 in whichR¹ is CH₃, R²and R³ are H, the SO₂ X group is attached to the carbon atom in the4-position and ##STR90## or a physiologically tolerable salt thereof. 6.An imidazole compound of the formula I as claimed in claim 1 wherein R⁵is morpholine, thiomorpholine or piperazine.
 7. An imidazole compound ofthe formula I as claimed in claim 1 wherein R⁴ and R⁵, together with theamide nitrogen to which they are bonded, form a thiomorpholine orpiperazine ring.
 8. A pharmaceutical composition for the prophylaxis ortreatment of circulatory disturbances and of the disorders resultingtherefrom, which comprises an effective amount of at least one compoundof the formula I as claimed in claim 1 or at least one physiologicallytolerable salt together with a physiologically acceptable excipient. 9.The pharmaceutical composition as claimed in claim 8 for the prophylaxisor treatment of disturbances of the microcirculation.
 10. A method forthe prophylaxis or treatment of circulatory disturbances and of thedisorders resulting therefrom, which comprises administering to a host apharmaceutical composition as claimed in claim
 8. 11. A method for theprophylaxis or treatment of circulatory disturbances and of thedisorders resulting therefrom, which comprises administering to a hostan effective amount of a compound of the formula I as claimed in claim1.